Project Summary The striatum is central to motivated behaviors and goal-directed actions. Neuromodulation by acetylcholine (ACh) plays a major role in regulating striatal circuits and resulting behaviors. ACh levels within the striatum are the highest in the CNS. Cholinergic transmission is involved in multiple basal ganglia based functions including the control of voluntary movement, motor and associative learning, as well as reward. Dysfunctions in acetylcholine (ACh) signaling in the striatum are associated with a variety of neurological movement disorders including Parkinson?s disease, Huntington?s disease, and dystonia. Identifying how these dysfunctions occur is limited by a lack of understanding of the basic mechanisms of cholinergic transmission. While both nicotinic and muscarinic receptors are expressed in the striatum, ACh does not directly evoke post-synaptic events at most synapses that can be detected with conventional electrophysiological approaches. Instead cholinergic receptors modulate striatal inputs or indirectly alter the excitability of post-synaptic neurons through multistep intracellular cascades. This proposal will examine the dynamics of ACh at muscarinic synapses using the viral expression of GIRK channels that was developed in the last funding period. The dynamics of ACh will be compared in control and disease states following loss of dopamine. The proposed studies are expected to be significant in that they have to potential to determine specific mechanisms that regulate cholinergic transmission and identify the dysregulations that occur in an animal model of Parkinson?s disease.